of the A and B waves [224]. The in vivo findings correlated well with the in vitro muscle strip findings, a cholinergic on contraction, and a non‐cholinergic off contraction [166, 225]. The cholinergic effect is mediated predominantly via a muscarinic M3 receptor [226], although the M2 receptor may also be involved [205, 227]. in vitro, the off contraction is associated with a membrane depolarization and spiking activity that follows hyperpolarization of the muscle [228–231, later shown to be due to the action of the inhibitory neurotransmitter NO or similar nitroso compound [232]. Very similar membrane events were observed with the peristaltic contraction in vivo [233–236]. Paired vagal stimulation demonstrated the functional inhibitory effect of one stimulus on the contraction of the other, depending on stimulus frequency and duration [237].
Further studies of muscle strips from along the smooth muscle esophagus have demonstrated regional differences in the smooth muscle responses to electrical stimulation and pharmacologic agents [166, 238, 239]: (i) with electrical stimulation, the duration of the inhibitory hyperpolarization is shorter in the proximal esophagus and longer distally, and therefore muscle depolarization and muscle contraction occur later distally; and (ii) atropine decreases the duration of the hyperpolarization and latency to the contraction in the proximal esophagus but not in the distal esophagus (Figure 5.12). This cholinergic effect to shorten the latency decreases progressively along the esophagus. These findings are mirrored in vivo. Atropine delays the onset of the peristaltic contractions and decreases amplitude in the proximal smooth muscle esophagus, the effect decreasing distally [210, 214, 217, 220]. On the other hand, blocking NO release and its inhibitory effect shortens the delay to the peristaltic contractions at each level and can decrease amplitude, the effect most pronounced distally [240–245].
Latency of proximal esophageal contraction is more susceptible to the anticholinergic agent atropine compared to the distal esophagus [166]. Similarly, blockade of NO synthase inhibits the latency and amplitude of contraction to increase the velocity of peristalsis in the distal smooth muscle esophagus more so than the proximal. This highlights a greater cholinergic gradient in the proximal esophagus, while the distal esophagus has greater nitrergic innervation [240]. However, the proportion of acetylcholinesterase‐positive nitrergic neurons does not change along the esophagus [246]. There are no synapses in the descending hyperpolarization pathway; instead, it is mediated through a single descending neuron [245]. The differences in responses of the esophageal smooth muscle in different regions could be the result of released neurotransmitters [155]. Thus, latency from swallow to contraction is controlled by the release of NO from inhibitory nerves [228], but the initiator of depolarization remains unclear. While release of acetylcholine by cholinergic neurons directly depolarizes smooth muscle, nitrergic neurons may also generate contraction through their passive rebound from hyperpolarization. Eicosanoids have also been shown to initiate nerve‐induced depolarization in the esophageal longitudinal muscles [236]. Several ion channels expressed on sensory afferent neurons in the esophagus modulate gastrointestinal motility [247, 248]. Secondary peristalsis and distention sensitivity are enhanced by the infusion of transient receptor potential vanilloid receptor 1 (TRPV1) agonist capsaicin, which increases the permeability of primary afferent neuron membranes to calcium [249]. On the other hand, infusion of the 5–HT4 agonist mosapride activates normal peristaltic reflex by inducing the release of neurotransmitters such as acetylcholine from postganglionic nerve endings of the myenteric plexus [250]. Enkephalins may also modulate peristalsis, through either inhibition or excitation of various neurotransmitters [251, 252]. Finally, catecholamines and CGRP are thought to play an inhibitory role in the control of esophageal contractions [252, 253].
Figure 5.12 Difference in the duration of the inhibitory junction potential along the opossum esophagus and the effect of atropine. Transmural stimulation produced an inhibitory junction potential (IJP) that was of longer duration at the distal site. Atropine prolonged the duration of the IJP at the proximal site with no effect on the duration at the distal site. The cholinergic effect at only the proximal site is compatible with a gradient of cholinergic activity along the esophagus.
Source: Goyal RK, Madhu P, Chang HY. Functional anatomy and physiology of swallowing and esophageal motility. In: Castell DO, Richter JE, eds. The Esophagus, 4th ed. © 2004, Wolters Kluwer.
Thus, the intramural neural mechanism combines a balance between a more prominent cholinergic excitatory effect proximally and a more prominent inhibitory nitrergic effect distally. This combination appears to play a major role in ensuring the distal propagation of the peristaltic wave (Figure 5.13). The two mechanisms also have clinical implications. Increased cholinergic effects have been implicated in spastic esophageal motor disorders, such as those with high‐amplitude contractions [126, 254]. Decreased or absent nitrergic innervation is a feature of LES dysfunction in achalasia [255]. The rapid or non‐peristaltic wave of achalasia is also in part attributed to absent or decreased nitrergic innervation, while accentuation of the inhibitory NO influence may contribute to slowed propagation velocity and decrease amplitude in the presence of esophagitis and endotoxemia [256, 257]. The exact mechanism whereby early and late sequential vagal discharges to the smooth muscle esophagus integrate with or exert control over local neural or myogenic mechanisms is not known.
Intramural myogenic (muscle) control mechanisms
Elsewhere in the gut, the myogenic control system has two fundamental characteristics: (i) electrical oscillations of the smooth muscle cells, usually called “slow waves”; and (ii) communication among smooth muscle cells allowing the tissue to operate as a functional unit [258, 259]. Both of these features are also present in the esophageal smooth muscle and can manifest with adequate cholinergic stimulation [165, 218, 219, 231, 260, 261]. A significant component of a myogenic system is contributed by the ICCs [131, 156]. It is not surprising, therefore, that with the esophagus isolated in vitro and with nerves blocked, a myogenic peristaltic contraction can be readily demonstrated in the smooth muscle segment [165, 218, 219, 262].
Regional gradients in the cholinergic and nitrergic innervation along the esophagus are believed to be sufficient for local control of peristalsis in the smooth muscle section. However, regional differences in the circular smooth muscle likely contribute to peristaltic contraction along the esophagus, including the responses to cholinergic and nitrergic innervation. These include a resting membrane potential gradient [228, 263], potassium and calcium ion channel diversity [251, 263, 264], and differences in muscle length–tension relationships and responses to cholinergic stimulation [264]. There are also differences in muscle proteins [265] and in intracellular signaling in response to cholinergic stimulation between esophageal body and LES muscle [266, 267].
Figure 5.13 Interplay of cholinergic (ACh) and non‐cholinergic (NANC) influences along the smooth muscle esophagus in the production of peristalsis. The cholinergic influence is most prominent proximally and decreases distally; the reverse is true for the NANC influence. Proximally, the contraction occurs earlier but is atropine sensitive, with cholinergic blockade delaying its appearance. Distally, the contraction normally appears later, but NANC blockade, such as with block of nitric oxide (NO) release, shortens the time to onset of the contraction. In either case of blockade, peristaltic velocity can significantly increase.